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MLH1  -  mismatch repair ATPase MLH1

Saccharomyces cerevisiae S288c

Synonyms: DNA mismatch repair protein MLH1, MutL protein homolog 1, PMS2, Post meiotic segregation protein 2, YM8520.16, ...
 
 
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Disease relevance of MLH1

 

High impact information on MLH1

  • Mlh3 is required for Mlh1 binding to meiotic chromosomes and localizes to meiotic chromosomes from the mid pachynema stage of prophase I [6].
  • Gene targeting studies in mice confirmed roles for Mlh1 and Pms2 in mammalian meiosis [7].
  • A yeast strain containing a mutation in the PCNA gene had a strongly elevated mutation rate in a dinucleotide repeat, and the rate was not further elevated in a strain also containing a mutation in MLH1 [8].
  • We show here that mutations in any three yeast genes involved in DNA mismatch repair (PMS1, MLH1 and MSH2) lead to 100- to 700-fold increases in tract instability, whereas mutations that eliminate the proof-reading function of DNA polymerases have little effect [9].
  • Previously, cytological analysis of MLH1-deficient mice has implied a role for Mlh1 in crossing-over during meiosis [10].
 

Biological context of MLH1

 

Anatomical context of MLH1

 

Associations of MLH1 with chemical compounds

  • Disruption of the MLH1 gene results in elevated spontaneous mutation rates during vegetative growth as measured by forward mutation to canavanine resistance and reversion of the hom3-10 allele [16].
  • Sensitivity to cisplatin and doxorubicin was increased in mlh1 mutant strains when the MLH1 gene was reintroduced, demonstrating a direct involvement of MMR proteins in sensitivity to these DNA-damaging agents [17].
  • The MLH1-PMS1 heterodimer then interacts with the MSH proteins at or near the mismatch site and is thought to act as a mediator to recruit downstream repair proteins [18].
  • Furthermore, two-hybrid analysis suggested that these ATP-binding-induced conformational changes promote an interaction between the NH(2) termini of Mlh1p and Pms1p [19].
  • Mlh1-Pms1 also binds to DNA, but independently of a mismatch [20].
 

Physical interactions of MLH1

  • MLH3 interacted with MLH1 in a two-hybrid system [21].
  • Using a yeast two-hybrid screen and a GST in vitro transcription and translation assay, the mismatch repair (MMR) protein Mlh1p was demonstrated to interact physically with Ntg2p [22].
  • Here we report yeast two-hybrid results suggesting that Exo1p can interact physically with MutLalpha through the Mlh1p subunit [23].
  • Three approaches, ATP hydrolysis assays, limited proteolysis protection, and equilibrium dialysis, provide evidence that the amino-terminal domain of Mlh1 binds ATP with >10-fold higher affinity than does the amino-terminal domain of Pms1 [24].
 

Regulatory relationships of MLH1

  • Overexpression of the PMS1 gene alone caused a moderate increase in the mutation rate and strongly suppressed the mutator effect caused by MLH1 overexpression [13].
 

Other interactions of MLH1

  • Taken together, these data imply modulation of a basic Mlh1 function via combination with the three other MutL homologs and suggest specifically that Mlh1 combines with Mlh3 to promote meiotic crossing-over [25].
  • In mlh1 Delta strains, heteroduplex rejection was greater than in msh6 Delta strains but less than in wild type [26].
  • Ntg2p, a Saccharomyces cerevisiae DNA N-glycosylase/apurinic or apyrimidinic lyase involved in base excision repair of oxidative DNA damage, interacts with the DNA mismatch repair protein Mlh1p. Identification of a Mlh1p binding motif [22].
  • Furthermore, S445A, F447A, and F448A mutants of Exo1p do not bind Mlh1p, but the wild type Exo1p does [22].
  • Previously, we reported evidence suggesting that Saccharomyces cerevisiae MutLalpha, composed of Mlh1p and Pms1p, was a functional member of the gyrase b/Hsp90/MutL (GHL) dimeric ATPase superfamily characterized by highly conserved ATPase domains [23].
 

Analytical, diagnostic and therapeutic context of MLH1

References

  1. Novel dominant mutations in Saccharomyces cerevisiae MSH6. Das Gupta, R., Kolodner, R.D. Nat. Genet. (2000) [Pubmed]
  2. The effect of genetic background on the function of Saccharomyces cerevisiae mlh1 alleles that correspond to HNPCC missense mutations. Wanat, J.J., Singh, N., Alani, E. Hum. Mol. Genet. (2007) [Pubmed]
  3. Functional domains of the Saccharomyces cerevisiae Mlh1p and Pms1p DNA mismatch repair proteins and their relevance to human hereditary nonpolyposis colorectal cancer-associated mutations. Pang, Q., Prolla, T.A., Liskay, R.M. Mol. Cell. Biol. (1997) [Pubmed]
  4. MLH1 mutations differentially affect meiotic functions in Saccharomyces cerevisiae. Hoffmann, E.R., Shcherbakova, P.V., Kunkel, T.A., Borts, R.H. Genetics (2003) [Pubmed]
  5. Purification of eukaryotic MutL homologs from Saccharomyces cerevisiae using self-affinity technology. Hall, M.C., Kunkel, T.A. Protein Expr. Purif. (2001) [Pubmed]
  6. Meiotic arrest and aneuploidy in MLH3-deficient mice. Lipkin, S.M., Moens, P.B., Wang, V., Lenzi, M., Shanmugarajah, D., Gilgeous, A., Thomas, J., Cheng, J., Touchman, J.W., Green, E.D., Schwartzberg, P., Collins, F.S., Cohen, P.E. Nat. Genet. (2002) [Pubmed]
  7. Mammalian MutS homologue 5 is required for chromosome pairing in meiosis. Edelmann, W., Cohen, P.E., Kneitz, B., Winand, N., Lia, M., Heyer, J., Kolodner, R., Pollard, J.W., Kucherlapati, R. Nat. Genet. (1999) [Pubmed]
  8. Requirement for PCNA in DNA mismatch repair at a step preceding DNA resynthesis. Umar, A., Buermeyer, A.B., Simon, J.A., Thomas, D.C., Clark, A.B., Liskay, R.M., Kunkel, T.A. Cell (1996) [Pubmed]
  9. Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair. Strand, M., Prolla, T.A., Liskay, R.M., Petes, T.D. Nature (1993) [Pubmed]
  10. Mlh1 is unique among mismatch repair proteins in its ability to promote crossing-over during meiosis. Hunter, N., Borts, R.H. Genes Dev. (1997) [Pubmed]
  11. Mutations in the MSH3 gene preferentially lead to deletions within tracts of simple repetitive DNA in Saccharomyces cerevisiae. Strand, M., Earley, M.C., Crouse, G.F., Petes, T.D. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  12. Systematic mutagenesis of the Saccharomyces cerevisiae MLH1 gene reveals distinct roles for Mlh1p in meiotic crossing over and in vegetative and meiotic mismatch repair. Argueso, J.L., Kijas, A.W., Sarin, S., Heck, J., Waase, M., Alani, E. Mol. Cell. Biol. (2003) [Pubmed]
  13. Inactivation of DNA mismatch repair by increased expression of yeast MLH1. Shcherbakova, P.V., Hall, M.C., Lewis, M.S., Bennett, S.E., Martin, K.J., Bushel, P.R., Afshari, C.A., Kunkel, T.A. Mol. Cell. Biol. (2001) [Pubmed]
  14. Contributions by MutL homologues Mlh3 and Pms2 to DNA mismatch repair and tumor suppression in the mouse. Chen, P.C., Dudley, S., Hagen, W., Dizon, D., Paxton, L., Reichow, D., Yoon, S.R., Yang, K., Arnheim, N., Liskay, R.M., Lipkin, S.M. Cancer Res. (2005) [Pubmed]
  15. Analysis of yeast pms1, msh2, and mlh1 mutators points to differences in mismatch correction efficiencies between prokaryotic and eukaryotic cells. Yang, Y., Karthikeyan, R., Mack, S.E., Vonarx, E.J., Kunz, B.A. Mol. Gen. Genet. (1999) [Pubmed]
  16. Dual requirement in yeast DNA mismatch repair for MLH1 and PMS1, two homologs of the bacterial mutL gene. Prolla, T.A., Christie, D.M., Liskay, R.M. Mol. Cell. Biol. (1994) [Pubmed]
  17. Dependence on RAD52 and RAD1 for anticancer drug resistance mediated by inactivation of mismatch repair genes. Durant, S.T., Morris, M.M., Illand, M., McKay, H.J., McCormick, C., Hirst, G.L., Borts, R.H., Brown, R. Curr. Biol. (1999) [Pubmed]
  18. Msh2 separation of function mutations confer defects in the initiation steps of mismatch repair. Kijas, A.W., Studamire, B., Alani, E. J. Mol. Biol. (2003) [Pubmed]
  19. Functional studies on the candidate ATPase domains of Saccharomyces cerevisiae MutLalpha. Tran, P.T., Liskay, R.M. Mol. Cell. Biol. (2000) [Pubmed]
  20. DNA binding properties of the yeast Msh2-Msh6 and Mlh1-Pms1 heterodimers. Drotschmann, K., Hall, M.C., Shcherbakova, P.V., Wang, H., Erie, D.A., Brownewell, F.R., Kool, E.T., Kunkel, T.A. Biol. Chem. (2002) [Pubmed]
  21. The Saccharomyces cerevisiae MLH3 gene functions in MSH3-dependent suppression of frameshift mutations. Flores-Rozas, H., Kolodner, R.D. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  22. Ntg2p, a Saccharomyces cerevisiae DNA N-glycosylase/apurinic or apyrimidinic lyase involved in base excision repair of oxidative DNA damage, interacts with the DNA mismatch repair protein Mlh1p. Identification of a Mlh1p binding motif. Gellon, L., Werner, M., Boiteux, S. J. Biol. Chem. (2002) [Pubmed]
  23. Interactions of Exo1p with components of MutLalpha in Saccharomyces cerevisiae. Tran, P.T., Simon, J.A., Liskay, R.M. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  24. Differential ATP binding and intrinsic ATP hydrolysis by amino-terminal domains of the yeast Mlh1 and Pms1 proteins. Hall, M.C., Shcherbakova, P.V., Kunkel, T.A. J. Biol. Chem. (2002) [Pubmed]
  25. Functional specificity of MutL homologs in yeast: evidence for three Mlh1-based heterocomplexes with distinct roles during meiosis in recombination and mismatch correction. Wang, T.F., Kleckner, N., Hunter, N. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  26. Heteroduplex rejection during single-strand annealing requires Sgs1 helicase and mismatch repair proteins Msh2 and Msh6 but not Pms1. Sugawara, N., Goldfarb, T., Studamire, B., Alani, E., Haber, J.E. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  27. Analysis of interactions between mismatch repair initiation factors and the replication processivity factor PCNA. Lee, S.D., Alani, E. J. Mol. Biol. (2006) [Pubmed]
  28. Human MutL homolog (MLH1) function in DNA mismatch repair: a prospective screen for missense mutations in the ATPase domain. Ellison, A.R., Lofing, J., Bitter, G.A. Nucleic Acids Res. (2004) [Pubmed]
  29. High affinity cooperative DNA binding by the yeast Mlh1-Pms1 heterodimer. Hall, M.C., Wang, H., Erie, D.A., Kunkel, T.A. J. Mol. Biol. (2001) [Pubmed]
 
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